This application claims priority to European Patent Application No. 01303347.7-2117, filed Apr. 10, 2001, the contents being incorporated by reference herein.
This invention relates to a novel intermediate which is valuable in the synthesis of a known medicament by a more advantageous route. The invention further relates to processes by which such an intermediate may first be itself prepared and thereafter may be converted into the known anti-depressant (xc2x1)-1-[2-dimethylamino-1-(4-methoxyphenyl)-ethyl]-cyclohexanol of structural formula (IX): 
and pharmacologically-acceptable salts thereof, e.g. Venlafaxine hydrochloride, supplied by American Home Products, Inc., under the trade name Effexor(copyright).
Venlafaxine selectively inhibits the neuronal uptake of serotonin-norepinephrine and to a lesser extent dopamine. Studies indicate that it has comparable or possibly slightly greater efficacy to other selective serotonin reuptake inhibitors (SSRI""s). It appears to be as effective as standard antidepressants such as imipramine. Venlafaxine""s unique chemical structure and neuro-pharmacological activity give it a broader spectrum of activity than other antidepressants.
Previously known methods for the preparation of Venlafaxine include e.g. that taught in EP 0,112,669, which discloses the preparation of various 2-aryl-2-(1-hydroxycyclohexyl)ethylamine derivatives via xcex1-aryl-xcex1-(1-hydroxy-cyclohexyl) acetonitriles or xcex1-aryl-N,N-dimethyl-xcex1-(1-hydroxycyclohexyl) acetamide as chemical intermediates. These chemical intermediates are prepared by condensing xcex1-arylacetonitriles or -aryl-N,N-dimethyl acetamides with cyclohexanone.
GB 2,227,743 discloses the preparation of 2-(1-hydroxycyclohexylethyl-thioacetamide) derivatives for the synthesis of Venlafaxine. The thioacetamido derivative is prepared from 4-methoxyacetophenone via Kindler modification of the Willgerodt reaction.
Zhou Jinpei et al. (Zhongguo Yaoke Daxue Xuebao (Journal of China) 1999, 30(4), 249-250) have reported the synthesis of Venlafaxine using methoxy-benzene as a starting material. The route involves 5 steps and gives 11% overall yield. In this route anisole is treated with chloroacetyl chloride under Friedel-Crafts acylation conditions followed by substitutions of xcex1-halo-p-methoxyacetophenone by dimethylamine which is reduced by potassium borohydride to give a xcex2-hydroxydimethylamine derivative. This intermediate, on treatment with PBr3 followed by magnesium in tetrahydrofuran (THF), and subsequent treatment with cyclohexanone, yields Venlafaxine.
These known synthetic routes tend to involve the use of hazardous, costly and moisture sensitive reagents. For example, the synthesis described in EP 0,112,669 requires a very low reaction temperature (xe2x88x9250xc2x0 C. to xe2x88x9270xc2x0 C.), and a hydrogenation step which uses expensive rhodium catalyst. Materials in this route are not easily available, and the reaction conditions are harsh, with high demands on equipment, and high production costs.
The process taught in GB 2,227,743 uses a ratio of 50:1 Raney nickel to thioamide in its hydrogenation step, and also requires the use of toxic solvents such as dioxane for the reduction of thioamide. These reagents and conditions make this process commercially unattractive.
Zhou Jinpei""s process requires the use of costly chemicals such as potassium borohydride and PBr3, as well as the purification of an important intermediate via distillation under high vacuum, which further adds to the cost.
We have now evolved a synthetic route for the preparation of Venlafaxine which starts from easily available materials, and employs mild reaction conditions and simple after-treatment procedures, thus making it suitable for large-scale production. In this new route, hazardous, moisture-sensitive, and highly inflammable reagents are completely avoided, as are costly chemicals such as rhodium catalyst and potassium borohydride.
Certain alternatives are available in the early stages of this route, which is indeed advantageous since it opens the way to the use of different reaction strategies, from a range of starting materials, which may be selected according to cost and availability. All of these alternative routes however pass through the same novel epoxy nitrile intermediate.
According to the present invention, there is provided the epoxy-nitrile compound of structural formula (I): 
namely 2-(4-methoxy-phenyl)-1-oxa-spiro[2.5]octane-2-carbonitrile.
The present invention also provides a process for the preparation of the compound of formula (I), in which (1-bromo-cyclohexyl)-(4-methoxy-phenyl)-methanone of structural formula (II): 
is subjected to treatment with a cyanation agent, so as to yield the epoxy nitrile intermediate of formula (I).
The cyanation agent employed is preferably sodium cyanide or potassium cyanide, although other cyanation agents may be used, such as trimethyl silyl cyanide, cuprous cyanide, other alkali and alkaline earth metal cyanides, or other cyanating agents known from the literature.
The reaction can be readily performed in solution in methanol at room temperature. Alternatively, solvents such as ethanol, isopropyl alcohol, acetonitrile, dimethyl formamide, dimethyl sulphoxide, dimethyl acetamide, hexamethylene phosphoric triamide (HMPT), ethyl acetate, or sulfolane, may be used, as may benzene, toluene, cyclohexane, dichloromethane, or chloroform, in the presence of a phase transfer catalyst. The phase transfer catalyst is required when using these non-polar solvents, as the solubility of inorganic cyanides therein is practically nil. The catalyst therefore acts so as to carry the cyanide ion to the organic phase for reaction.
The reaction may be carried out at a temperature in the range of from xe2x88x9210xc2x0 C. to 60xc2x0 C. Preferably the reaction temperature is in the range of from 20xc2x0 C. to 25xc2x0 C.
The reaction time may be in the range of from 2 to 48 hours, or more preferably is in the range of from 6 to 8 hours.
The ratio of solvent to (1-bromo-cyclohexyl)-(4-methoxyphenyl)-methanone (II) may be in the range of from 1:1 to 100:1. Preferably the ratio used is substantially 25:1.
Preferably, the process additionally comprises a further step of previously preparing the compound of formula (II), by subjecting cyclohexyl-(4-methoxy-phenyl)-methanone of structural formula (III): 
to treatment with an xcex1-keto-halogenating agent, so as to give the compound of formula (II). A reaction for the preparation of the bromo-ketone (II) is reported in Bull. Soc. Chim. France (1962) 90-6.
The xcex1-keto-halogenation is preferably effected using phenyltrimethyl ammonium perbromide. Alternatively, a brominating agent may be selected from liquid bromine, N-bromo succinimide, 1,3-dibromo-5,5-dimethyl-hydantoin, quaternary ammonium and phosphonium perbromides, N-chlorosuccinimide, and other halogenating agents known in the literature.
The solvent used may be selected from methanol, acetic acid, benzene, toluene, chloroform, carbon tetrachloride, tetrahydrofuran (THF), acetonitrile, ethanol, dichloromethane, dioxane, t-butanol, and substituted benzenes.
The reaction is preferably carried out at a temperature of substantially 68xc2x0 C., for a time of about 6 hours.
The ratio of solvent to ketone may be in the range of from 1:1 to 100:1, but preferably is substantially 20:1.
At this point it should be noted that the starting point for the above-described stage in the overall syntheses, namely cyclohexyl-(4-methoxy-phenyl)-methanone of formula (III), is itself a known compound, disclosed in Izv.Akad.Nauk Turkm.SSR.Ser.Fiz-Tekhn.,Khim.iGeol.Nauk 1963, No. 1,115-6. The overall process of the present invention therefore may include an additional step of subjecting methoxy-benzene of structural formula (IV): 
to Friedel-Crafts acylation treatment so as to yield the compound of formula (III).
Thus, the cyclohexyl-(4-methoxy-phenyl)-methanone (III) may for instance be synthesized by Friedel-Crafts reaction between cyclohexane-carbonyl chloride and methoxy-benzene in the present of aluminium trichloride: 
Alternatively, boron trifluoride or sodium aluminium chloride may also be used as the Friedel-Crafts reagent, in place of aluminium trichloride.
The solvent is selected from methoxy-benzene and halogenated or nitrated benzenes, and may be used in a ratio relative to the cyclohexane-carbonyl chloride in the range of from 5:1 to 50:1.
The reaction temperature may be in the range of from xe2x88x9220xc2x0 C. to 40xc2x0 C.
However, unless there are other, external reasons that argue for the use of methoxy-benzene as the primary starting material for the overall syntheses, we currently believe that the intermediate cyclohexyl-(4-methoxy-phenyl)-methanone (III) may usually be better produced in an alternative manner.
It is thus preferred that the previously-outlined process of this invention should instead further comprise an additional step of subjecting cyclohexyl-(4-methoxy-phenyl)-methanol of structural formula (V): 
to oxidation so as to yield the cyclohexyl-(4-methoxy-phenyl)-methanone (III).
Oxidation is preferably performed using chromic acid, which may desirably be formed in situ by the reaction of sodium dichromate dihydrate with sulphuric acid. Alternatively, an oxidising agent may be selected from alkali and alkaline earth metal chromates and dichromates, chromic anhydride, manganese dioxide, alkali and alkaline earth metal manganates, permanganates, nitric acid, alkali and alkaline earth metal persulphates, quaternary ammonium and phosphonium manganates and permanganates, chromates and other oxidising agents known in the literature.
The oxidation is preferably carried out at a temperature in the range of from 25xc2x0 C. to 30xc2x0 C., for a time of substantially 3 hours.
This alternative process preferably further comprises the initial step of subjecting 4-methoxy-benzaldehyde of structural formula (VI): 
to treatment with a cyclohexyl magnesium halide, C6H11xe2x80x94Mgxe2x80x94X (where X=chlorine, bromine or iodine) so as to yield cyclohexyl-(4-methoxy-phenyl)-methanol (V). The reaction is preferably carried out using cyclohexyl magnesium bromide in THF at a temperature in the range of from 10xc2x0 C. to 15xc2x0 C. for a period of substantially one hour. The cyclohexyl magnesium bromide may desirably be formed in situ by the reaction of cyclohexyl bromide with magnesium turnings.
Alternatively, the 4-methoxy-benzaldehyde (VI) may be treated with an organometallic reagent such as cyclohexyl lithium or dialkylcupro lithium. Besides THF, the solvent used may also be selected from diethyl ether, dibutyl ether, dipropyl ether, di-isoproyl ether, dioxane, diglyme, or alkylated polyethers.
An alternative preparation of cyclohexyl-(4-methoxy-phenyl)-methanol (V) may be performed by treating the compound of formula (XI): 
namely cyclohexanecarbaldehyde, with anisyl magnesium halide or anisyl lithium.
In a quite different alternative process according to the present invention, the compound corresponding to formula (VII): 
namely cyclohexylidene-(4-methoxy-phenyl)-acetonitrile, is treated with an epoxidating agent, such as m-chloroperbenzoic acid (m-CPBA) to yield the desired compound of formula (I).
The epoxidating agent may alternatively be selected from perbenzoic acid, peracetic acid, performic acid and other organic peracids, hydrogen peroxide, persulphuric acid, alkylhydroperoxides, and other epoxidating agents known in the literature.
The solvent for the epoxidation is selected from dichloromethane, dichloroethane, carbon tetrachloride, chloroform, ethyl acetate and toluene. Preferably, the solvent used is dichloromethane.
The reaction temperature may be in the range of from 0xc2x0 C. to the reflux temperature of the corresponding solvent but will preferably be substantially 40xc2x0 C. The reaction time may be in the range of from 1 hour to 48 hours, but will preferably be in the range of from 6 to 8 hours.
Preferably, the second alternative process further comprises a previous step of preparing the compound of formula (VII), by treating the compound corresponding to formula (VIII): 
namely (4-methoxy-phenyl)-acetonitrile, with cyclohexanone and a condensing agent such as sodium methoxide, to secure the compound of formula (VII). This reaction is reported in U.S. Pat. No. 2,647,122.
The condensing agent may alternatively be selected from sodium ethoxide, potassium t-butoxide, quaternary ammonium hydroxide and other alkali and alkaline earth metal alkoxides, alkali and alkaline earth metal hydrides, alkali and alkaline earth metal amides.
The solvent may be selected from methanol, ethanol, t-butanol and other solvents known to the art. Preferably methanol is used.
The reaction time may be in the range of from 1 to 24 hours, but preferably is in the range of from 3 to 6 hours.
The reaction temperature may be in the range of from 10xc2x0 C. to 60xc2x0 C., but is preferably room temperature, that is to say substantially 25xc2x0 C.
A further possible alternative process for the preparation of 2-(4-methoxy-phenyl)-1-oxa-spiro[2.5]octane-2-carbonitrile (I), comprises subjecting the compound corresponding to formula (XII): 
namely chloro-(4-methoxy-phenyl)-acetonitrile, to Darzen""s condensation (i.e. halohydrin formation, followed by cyclization), using cyclohexanone in the presence of a base.
The compound of formula (I), when thus prepared by any of the alternative processes as described above, may desirably be used as an intermediate in the preparation of the compound corresponding to formula (IX): 
namely (xc2x1)-1-[2-dimethylamino-1-(4-methoxy-phenyl)-ethyl]-cyclohexanol.
According to a further aspect of the present invention there is therefore provided a process for the preparation of the compound of structural formula (IX), which comprises the steps of:
(a) hydrogenating the epoxy-nitrile of structural formula (I) in the presence of a catalyst, so as to yield 1-[2-amino-1-(4-methoxy-phenyl)-ethyl]-cyclohexanol corresponding to formula (X): 
and
(b) treating the 1-[2-amino-1-(4-methoxy-phenyl)-ethyl]-cyclohexanol (X) produced by step (a) above with formaldehyde and formic acid, in the presence of water;
to yield the desired (xc2x1)-1-[2-dimethylamino-1-(4-methoxy-phenyl)-ethyl]-cyclohexanol.
The hydrogenation is preferably effected in the presence of Raney nickel catalyst, at a pressure in the range of from 500 to 1000 kPa. The ratio of Raney nickel to epoxy nitrile (I) may be in the range of from 5:1 to 1:5 by weight. Preferably, the ratio used is substantially 1:1.
Alternatively, the hydrogenation may be carried out using a reagent selected from platinum dioxide, platinum and palladium and nickel on different inert supports, aluminium hydride, lithium aluminium hydride, sodium borohydride, potassium borohydride, lithium borohydride in the presence of Lewis acids, or quaternary ammonium borohydrides, neat or in the presence of a phase transfer catalyst.
The hydrogenation reaction may be carried out at a temperature in the range of from 0xc2x0 C. to 100xc2x0 C., but is preferably carried out at room temperature.
The solvent may be selected from tetrahydrofuran (THF), dioxane, glyme, dialkylethers, polyethers and ethyl acetate.
Alternatively, the epoxynitrile (I) can be reduced to the desired amino compound (X) by treating it with ammonium formate and hydrogen, in the presence of a catalyst selected from noble metal or supported noble metal catalysts.
The treatment of compound (X) with formaldehyde and formic acid in step (b) is best performed at a temperature of substantially 100xc2x0 C. for a time of substantially 6 hours, so as to yield 1-[2-dimethylamino-1-(4-methoxy-phenyl)-ethyl]-cyclohexanol of formula (IX), or Venlafaxine.
Alternatively, the epoxynitrile of structural formula (I) may be reduced to a hydroxynitrile intermediate of structural formula (XIII): 
namely (1-hydroxy-cyclohexyl)-(4-methoxy-phenyl)-acetonitrile, using ammonium formate and a noble metal or supported noble metal catalyst. This hydroxynitrile compound (XIII) is then further reduced to the corresponding amino compound of formula (X) by treatment with Raney nickel, platinum dioxide, palladium, cobalt boride, nickel boride, or other suitable catalysts known from the literature.